If you validated the drug target to cure a disease, but can’t hit it efficiently with high-throughput screening (HTS), fragment-based drug discovery could be your answer. It has established itself as a reliable method in identifying compounds for novel or hard to hit target classes with the registration of the skin cancer drug Zelboraf (Vemurafenib) to target B-RafV600E melanoma.

No doubt, HTS has lead to amazing breakthroughs in drug discovery in the past decades. However, it has its limits in the identification of protein-protein interaction inhibitors. As recently reviewed by Drysdale et al., the latest research in this field demonstrate that this is the area where fragment-based drug discovery has its clear advantages over HTS [1]. In addition, whereas the latter needs to understand and make use of the target mechanism of action to identify small molecule compounds, fragment-based drug discovery is based on a biophysical screening process: The determination of the three-dimensional experimental binding mode of low-molecular-weight ligands to its target using X-ray crystallography or NMR spectroscopy.

A good example for the reliability of the fragment-based screening method is the targeting of Hsp90. The biophysical screening method identified chemotypes comparable to the published clinical candidates.

More striking, whereas HTS failed to give any useful starting-points, fragment-based drug discovery has identified compounds binding directly to K-RAS, one of the most mutated and validated targets in cancer. In addition, the latter screening method required fewer compounds to be screened compared to high-throughput-screening.

Another convincing case for the advances of fragment-based drug discovery is the identification of compounds inhibiting ß-secretase for the potential treatment of Alzheimer’s disease. In this arena, HTS had so far produced limited results.

The list of compounds in clinical development resulting from fragment-based drug discovery is growing and the registration of Zelbraf to target B-RafV600E melanoma might just be the beginning of a new era in drug discovery.

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